Robo (expressed on neurons) and Slit (expressed by midline glia) are a receptor and repulsive ligand, respectively, that help control midline crossing and cellular migration of neurons during development (and mesodermal cells during the development of other organs and tissues). However, Drosophila slit and robo mutants have different phenotypes, suggesting that there may be additional receptors for Slit: slit causes all axons to enter the midline and not leave, robo causes aberrant crossing and recrossing of the midline. Two groups (Rajagopalan et al. and Simpson et al.) have characterized two additional Robo receptors, Robo2 and Robo3, in Drosophila for their roles in controlling neuronal migration and midline crossing and the formation of the longitudinal fascicles. Both groups showed that Robo and Robo2 double mutants recapitulate the slit phenotype, and they analyze the expression patterns of the robo genes. The three robo genes are expressed at different stages of development with unique and overlapping patterns of expression in different cells. This differential expression of Robo proteins or "Robo code" provides a complex interplay and regulatory mechanism for cellular interpretation of the repulsive Slit signal. Simpson et al. also identified a biphasic effect of Robo2 dosage: low doses cause inappropriate crossing of the midline, high doses cause a commissureless phenotype where no axons cross the midline. Simpson et al. suggest that low doses of Robo2 interfere with Robo signaling resulting in a partial robo loss-of-function phenotype, whereas high enough levels of Robo2 are sufficient to transmit a repulsive signal. Kinrade et al. focused their attention on the role of Robo in glial migration along the midline in Drosophila embryos. They found that Robo is expressed transiently by glia early in development and that loss of Robo function results in the glia of the most medial fascicle inappropriately crossing the midline. Furthermore, whereas the initial trajectory of the most medial, longitudinal fascicle is directed in a Robo-dependent manner by the pioneer neuron, the maintenance of the longitudinal trajectory of the follower neurons is dependent on trophic interactions between the longitudinal glia and the neurons. When the pioneer neuron is ablated, then both the longitudinal glia and the axons of the longitudinal fascicle cross the midline despite the expression of Robo by the longitudinal neurons. As Rusch and Van Vactor put it, neuronal migration along the midline is regulated by the Robo code and, according to Kinrade et al., enforced by trophic interactions between glia and neuron.
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